The present invention provides pyrazine derivatives that inhibit tyrosine kinase activity. Certain pyrazine derivatives are selective inhibitors of the vascular endothelial growth factor (VEGF) receptor tyrosine kinase. The present invention also provides pharmaceutical formulations containing the pyrazine derivatives and methods for use of these formulations as anti-tumor agents, and to treat diabetic retinopathy, rheumatoid arthritis, endometriosis, and psoriasis.
Angiogenesis plays a role in various processes including development of the vasculature, wound healing and maintenance of the female reproductive system. Pathological angiogenesis is associated with disease states such as cancer, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis. Solid-tumor cancers, in particular, are dependent on angiogenesis for their growth. The vascular endothelial growth factors (VEGFs) are mediators of both normal and pathologic angiogenesis. VEGF transmits signals into cells through their cognate receptors, which belong to the receptor tyrosine kinase (RTK) family of transmembrane receptors. These receptors are tripartite, consisting of an extracellular ligand-binding domain, a transmembrane domain, which anchors the receptor in the membrane of the cell, and an intracellular tyrosine kinase domain. One subfamily of RTKs comprises the receptors Flt1/VEGF-R1 and KDR/Flk1/VEGF-R2, which bind VEGFs. Binding of the VEGF ligand to the receptor results in stimulation of the receptor tyrosine kinase activity and transduction of biological signals into the cell. The KDR/Flk1/VEGF-R2 receptor mediates the biological activities of mitogenesis and proliferation of endothelial cells while the Flt1/VEGF-R1 receptor mediates functions such as endothelial cell adhesion. Inhibition of KDR/Flk1/VEGF-R2 signalling has been shown to inhibit the process of angiogenesis. Inhibitors of this receptor are likely useful in controlling or limiting angiogenesis.
The present invention provides pyrazine derivative compounds that display activity as kinase inhibitors of the formula: 
where the substituents are defined herein. These pyrazine derivatives are useful as kinase inhibitors; particularly, as inhibitors against the kinase domain of the Vascular Endothelial Growth Factor Receptor (VEGF-R), inhibiting the activity of the VEGF receptor in vitro and in vivo.
In a preferred embodiment, the invention relates to compounds of Formula 1: 
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of cycloalkyl, heterocyclyl, biheterocyclyl, aryl, biaryl, heteroaryl and biheteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, lower alkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy;
A is selected from the group consisting of xe2x80x94N(R4)(CH2)xxe2x80x94, xe2x80x94O(CH2)xxe2x80x94, xe2x80x94S(CH2)xxe2x80x94, xe2x80x94SO2(CH2)xxe2x80x94, xe2x80x94SO2N(CH2)xxe2x80x94, xe2x80x94NSO2(CH2)xxe2x80x94, xe2x80x94N(R4)(CH2)xxe2x80x94, xe2x80x94N(R4)(CH2)1-4NH(CH2)xxe2x80x94, xe2x80x94N(R4)CONH(CH2)xxe2x80x94 and xe2x80x94N(R4)CNNH(CH2)xxe2x80x94; wherein x is an integer from 0 to 4;
R4 is selected from the group consisting of H, lower alkyl, alkyl, hydroxyalkyl, alkoxyalkyl, arylalkyl, lower alkenyl, alkenyl, aryl and heteroaryl; wherein aryl and heteroaryl are optionally substituted with 1 to 5 substituents independently selected from the group consisting of OH, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, alkyl, lower alkyl, alkoxy, lower alkoxy, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy;
R2 is selected from the group consisting of heteroaryl and biheteroaryl optionally substituted with 1 to 2 substituents independently selected from R7 and 1 substituent selected from R8;
R7 is selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy;
R8 is selected from the group consisting of alkyl, OH, hydroxyalkyl, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, alkylcarbonylamino, alkylcarbonyl, alkoxycarbonyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, O(CH2)nR5, O(CH2)nO(CH2)mR5, O(CH2)nCH[(CH2)mR5]2, O(CH2)nN[(CH2)mR5]2, OCON[(CH2)mR5]2, NH(CH2)nR5, NH(CH2)nCH(R5)2, NH(CH2)nSO2(CH2)mR5, NH(CH2)nO(CH2)mR5, NH(CH2)nOCH[(CH2)mR5]2, NH(CH2)nO(CH2)mO(CH2)mR5, NH(CH2)nN[(CH2)mR5]2, NH(CH2)nSO2NH(CH2)mR5, NH(CH2)nCH(OH)(CH2)mR5, NH(CH2)nCH(OH)(CH2)mOR5, NH(CH2)nCH(OH)(CH2)mN[(CH2)mR5]2, NH(CH2)nCO(CH2)mN[(CH2)mR5]2, NH(CH2)nCO2(CH2)mR5, NH(CH2)nCO(CH2)mSO2NH(CH2)mR5, NHCO(CH2)nCH(R5)2, NHCO(CH2)nR5, NHCO(CH2)nO(CH2)mR5, NHCO(CH2)nO(CH2)mO(CH2)mR5, NHCO(CH2)nO(CH2)mCO(CH2)mR5, NHCO(CH2)nN[(CH2)mR5]2, CONH(CH2)nO(CH2)mR5, and CONH(CH2)nN[(CH2)mR5]2; wherein n is an integer from 0 to 6 and m is an integer from 0 to 4; with the proviso, that m is at least 1 when R5 is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino;
R5 is selected from the group consisting of H, OH, lower alkyl, amino, alkylamino, di(alkyl)amino, aryl, heteroaryl, biheteroaryl and heterocyclyl; wherein aryl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, lower alkyl, acyl, carboxyl, aryl (optionally substituted with 1 to 5 halogen substituents), OH, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl and aminosulfonylalkyl; and, wherein heterocyclyl is further optionally substituted with 1 to 3 oxo substituents; and, R3 is selected from the group consisting of H, alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy.
In one aspect of this embodiment, the compound of claim 1 includes R1 wherein R1 is selected from the group consisting of cycloalkyl, heterocyclyl, biheterocyclyl, aryl, biaryl, heteroaryl and biheteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, lower alkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, alkoxycarbonyl, aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, (hydroxyalkyl)carbonyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy.
In another aspect of this embodiment, R1 is selected from the group consisting of aryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of lower alkyl, lower alkoxy, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, OH, halogen, cyano, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, carbamoyl, acyl, alkoxycarbonyl, aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy.
Preferably R1 is selected from the group consisting of phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of lower alkyl, lower alkoxy, OH, halogen, cyano, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, carbamoyl, acyl, alkoxycarbonyl, aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy. In another aspect, R1 is selected from the group consisting of phenyl optionally substituted with 1 to 5 substituents independently selected from the group consisting of methoxy, chlorine and fluorine. Still further in a preferred aspect of this embodiment, A is selected from the group consisting of xe2x80x94N(R4)(CH2)xxe2x80x94, xe2x80x94O(CH2)xxe2x80x94, xe2x80x94S(CH2)xxe2x80x94, xe2x80x94SO2(CH2)xxe2x80x94, xe2x80x94SO2N(CH2)xxe2x80x94, xe2x80x94NSO2(CH2)xxe2x80x94, xe2x80x94N(R4)(CH2)1-4O(CH2)xxe2x80x94 and xe2x80x94N(R4)(CH2)1-4NH(CH2)xxe2x80x94; wherein x is an integer from 0 to 3. In another aspect, A is selected from the group consisting of xe2x80x94N(R4)(CH2)xxe2x80x94, xe2x80x94O(CH2)xxe2x80x94, xe2x80x94S(CH2)xxe2x80x94, xe2x80x94SO2(CH2)xxe2x80x94, xe2x80x94SO2N(CH2)xxe2x80x94, xe2x80x94NSO2(CH2)xxe2x80x94, xe2x80x94N(R4)(CH2)1-4O(CH2)xxe2x80x94 and xe2x80x94N(R4)(CH2)1-4NH(CH2)xxe2x80x94; wherein x is an integer from 0 to 1. Alternatively, A is selected from the group consisting of xe2x80x94N(R4)(CH2)xxe2x80x94 and xe2x80x94O(CH2)xxe2x80x94; wherein x is an integer from 0 to 1.
Preferably, R4 is selected from the group consisting of H, alkyl, lower alkyl, alkoxyalkyl, alkenyl, lower alkenyl, hydroxyalkyl, aryl, arylalkyl and heteroaryl and still more preferably R4 is selected from the group consisting of H, lower alkyl and hydroxyalkyl. Most preferably, R4 is H.
In another aspect of this embodiment, R2 is selected from the group consisting of heteroaryl and biheteroaryl optionally substituted with 1 to 2 substituents independently selected from R7 and optionally substituted with 1 substituent selected from R8; wherein R7 is substituted on the 2 or 6 position from the point of attachment of R2; and, wherein R8 is substituted on a carbon atom at the 4 or 5 position from the point of attachment of R2. Preferably R2 is selected from the group consisting of heteroaryl optionally substituted with 1 substituent selected from R7 and substituted with 1 substituent selected from R8; wherein R7 is substituted on the 2 or 6 position from the point of attachment of R2; and, wherein R8 is substituted on a carbon atom at the 4 or 5 position from the point of attachment of R2.
In one aspect R2 is selected from the group consisting of thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl optionally substituted with 1 substituent selected from R7 and substituted with 1 substituent selected from R8; wherein R7 is substituted on the 2 or 6 position from the point of attachment of R2; and, wherein R8 is substituted on a carbon atom at the 4 or 5 position from the point of attachment of R2. Preferably R2 is selected from the group consisting of pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl optionally substituted with 1 substituent selected from R7 and substituted with 1 substituent selected from R8; wherein R7 is substituted on the 2 or 6 position from the point of attachment of R2; and, wherein R8 is substituted on a carbon atom at the 4 or 5 position from the point of attachment of R2.
Also preferably R7 is selected from the group consisting of lower alkyl, lower alkoxy, heterocyclylalkyl, aryl, arylalkyl, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, acyl, carboxyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy. In a preferred embodiment, R7 is selected from the group consisting of lower alkyl, OH, halogen, cyano, nitro, amino, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy. In yet another embodiment, R7 is selected from the group consisting of methyl, ethyl, OH, bromine, chlorine, fluorine, cyano, nitro, amino, trifluoromethyl and trifluoromethoxy.
R8 is preferably selected from the group consisting of OH, amino, (hydroxyalkyl)amino, alkoxycarbonyl, OCON[(CH2)mR5]2, NH(CH2)nR5, NH(CH2)nCH(R5)2, NH(CH2)nSO2(CH2)mR5, NH(CH2)nO(CH2)mR5, NH(CH2)nOCH[(CH2)mR5]2, NH(CH2)nO(CH2)mO(CH2)mR5, NH(CH2)nN[(CH2)mR5]2, NH(CH2)nSO2NH(CH2)mR5, NH(CH2)nCH(OH)(CH2)mR5, NH(CH2)nCH(OH)(CH2)mOR5, NH(CH2)nCH(OH)(CH2)mN[(CH2)mR]2, NH(CH2)nCO(CH2)mN[(CH2)mR5]2, NH(CH2)nCO2(CH2)mR5, NH(CH2)nCO(CH2)mSO2NH(CH2)mR5, NHCO(CH2)nR5, NHCO(CH2)nO(CH2)mR5, NHCO(CH2)nO(CH2)mO(CH2)mR5, NHCO(CH2)nO(CH2)mCO(CH2)mR5, CONH(CH2)nO(CH2)mR5 and CONH(CH2)nN[(CH2)mR5]2; wherein n is an integer from 0 to 6 and m is an integer from 0 to 4; with the proviso, that m is at least 1 when R5 is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino. In one aspect of this embodiment, R8 is selected from the group consisting of OH, amino, (hydroxyalkyl)amino, alkoxycarbonyl, OCON[(CH2)mR5]2, NH(CH2)nR5, NH(CH2)nCH(R5)2, NH(CH2)nSO2(CH2)mR5, NH(CH2)nO(CH2)mR5, NH(CH2)nOCH[(CH2)mR5]2, NH(CH2)nO(CH2)mO(CH2)mR5, NH(CH2)nN[(CH2)mR5]2, NH(CH2)nSO2NH(CH2)mR5, NH(CH2)nCH(OH)(CH2)mR5, NH(CH2)nCH(OH)(CH2)mOR5, NH(CH2)nCH(OH)(CH2)mN[(CH2)mR5]2, NH(CH2)nCO(CH2)mN[(CH2)mR5]2, NH(CH2)nCO2(CH2)mR5, NH(CH2)nCO(CH2)mSO2NH(CH2)mR5, NHCO(CH2)nR5, NHCO(CH2)nO(CH2)mR5, NHCO(CH2)nO(CH2)mO(CH2)mR5, NHCO(CH2)nO(CH2)mCO(CH2)mR5, CONH(CH2)nO(CH2)mR5 and CONH(CH2)nN[(CH2)mR5]2; wherein n is an integer from 0 to 5 and m is an integer from 0 to 2; with the proviso, that m is at least 1 when R5 is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino. Still more preferably, R8 is selected from the group consisting of OH, amino, (2-hydroxyethyl)amino, (3-hydroxy-n-propyl)amino, (4-hydroxy-n-butyl)amino, ethoxycarbonyl, OCON(R5)2, NH(CH2)1-4R5, NH(CH2)1-3SO2(CH2)0-1R5, NH(CH2)1-3O(CH2)0-1R5, NH(CH2)1-4OCH[(CH2)1-2R5]2, NH(CH2)1-3O(CH2)1-2O(CH2)1-2R5, NH(CH2)1-4N[(CH2)0-2R5]2, NH(CH2)1-4SO2NH(CH2)1-2R5, NH(CH2)1-4CH(OH)(CH2)1-2R5, NH(CH2)1-4CH(OH)(CH2)1-2OR5, NH(CH2)1-4CH(OH)(CH2)1-2N[(CH2)0-1R5]2, NH(CH2)1-3CO(CH2)0-1N[(CH2)0-1R5]2, NH(CH2)1-3CO2(CH2)0-1R5, NH(CH2)1-4CO(CH2)1-2SO2NH(CH2)1-2R5, NHCO(CH2)0-1R5, NHCO(CH2)1-3O(CH2)0-2R5, NHCO(CH2)1-2O(CH2)1-2O(CH2)1-2R5, NHCO(CH2)1-2O(CH2)0-1CO(CH2)1-2R5, CONH(CH2)1-3O(CH2)0-2R5 and CONH(CH2)1-3N[(CH2)1-2R5]2; with the proviso, that the R5 alkylene linking group is at least methylene when R5 is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino.
In another embodiment of this invention, R5 is selected from the group consisting of H, OH, lower alkyl, amino, alkylamino, di(alkyl)amino, aryl, heteroaryl and heterocyclyl; wherein aryl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, acyl, carboxyl, aryl (optionally substituted with one halogen substituent), di(alkyl)amino; alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl and aminosulfonylalkyl; and, wherein heterocyclyl is further optionally substituted with 1 to 3 oxo substituents. Preferably R5 is selected from the group consisting of H, OH, lower alkyl, heteroaryl and heterocyclyl; wherein heterocyclyl is optionally substituted with 1 to 3 substituents independently selected from the group consisting of lower alkyl, acyl, carboxyl, aryl (optionally substituted with one halogen substituent), di(alkyl)amino, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl, aminosulfonylalkyl and oxo. In a preferred embodiment, R5 is selected from the group consisting of H, OH, methyl, ethyl, t-butyl, 1H-azetidinyl, 1H-pyrrolidinyl, 4-tetrahydro-2H-pyranyl, hexahydro-1H-azepinyl, 1,3-dioxolanyl, 1,3-dioxanyl, piperidinyl, piperazinyl, imidazolyl, pyrazolyl, triazolyl and pyridinyl; wherein 1,3-dioxolanyl, 1,3-dioxanyl, piperazinyl and piperidinyl are optionally substituted with 1 to 2 substituents independently selected from the group consisting of methyl, acetyl, carboxyl, phenyl (optionally substituted with chlorine), di(methyl)amino, methylsulfonyl, methylaminosulfonyl and oxo.
In other embodiments, R3 is selected from the group consisting of H, lower alkyl, lower alkoxy, OH, halogen, cyano, amino, alkylamino and di(alkyl)amino. Preferably, R3 is selected from the group consisting of H, lower alkyl, lower alkoxy, OH, halogen, amino and di(alkyl)amino and more preferably, R3 is selected from the group consisting of H and methyl.
Preferred compounds include:
3-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-11-propanol;
3-[[5-[2-[(3-chlorophenyl)amino]-6-methyl-4-pyrimidinyl]-3-pyridinyl]amino]-1-propanol;
2-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-ethanol;
4-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-1-butanol;
3-[[5-[6-[(3-fluorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-1-propanol;
3-[[5-[6-[(3-methoxyphenyl)amino]pyrazinyl]-3-pyridinyl]amino]-1-propanol;
3-[[5-[6-[(phenylmethyl)amino]pyrazinyl]-3-pyridinyl]amino]-1-propanol;
3-[[6xe2x80x2-[(3-chlorophenyl)amino][2,2xe2x80x2-bipyrazin]-6-yl]amino]-1-propanol;
3-[[4-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-1-propanol;
3-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-2-thiazolyl]amino]-1-propanol; and,
2-[2-[2-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]ethoxy]ethoxy]-ethanol.
Additional preferred compounds include:
6-(5-amino-3-pyridinyl)-N-(3-chlorophenyl)-2-pyrazinamine;
Nxe2x80x2-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-N2,N2-dimethyl-1,2-ethanediamine;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-4-morpholinepropanamine;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-N3,N3-dimethyl-1,3-propanediamine;
N-(3-chlorophenyl)-6-[5-[[3-(1-piperazinyl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[4-(4-pyridinyl)butyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[3-(4-pyridinyl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[3-(3-pyridinyl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[3-(1H-pyrazol-1-yl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[3-(1H-1,2,4-triazol-1-yl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[3-(1H-imidazol-1-yl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[(tetrahydro-2H-pyran-4-yl)methyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3-chlorophenyl)-6-[5-[[2-(2-methoxyethoxy)ethyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(4-methoxyphenyl)-6-[5-[[3-(4-pyridinyl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-(3,4-dichlorophenyl)-6-[5-[[3-(4-pyridinyl)propyl]amino]-3-pyridinyl]-2-pyrazinamine;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-2-(2-methoxyethoxy)acetamide;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-2-ethoxy-acetamide;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-3-methoxy-propanamide; and,
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-2-hydroxy-acetamide.
Further preferred compounds include:
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-2-methoxy-acetamide;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-3-pyridinecarboxamide;
N-[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]-1-pyrrolidinecarboxamide; and,
4-[[5-[6-[(3-chlorophenyl)amino]pyrazinyl]-3-pyridinyl]amino]-butanoic acid ethyl ester.
In another aspect of the invention, the invention relates to compounds of Formula 2: 
or a pharmaceutically acceptable salt thereof, wherein
R1 is selected from the group consisting of cycloalkyl, heterocyclyl, biheterocyclyl, aryl, biaryl, heteroaryl and biheteroaryl optionally substituted with 1 to 5 substituents independently selected from the group consisting of alkyl, lower alkyl, alkenyl, alkynyl, alkoxy, lower alkoxy, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heterocyclylalkynyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heteroarylalkynyl, heteroarylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, alkylaminoalkyl, alkylaminoalkylamino, aminoalkyl, aminoalkylamino, di(alkyl)amino, di(alkyl)aminoalkyl, di(alkyl)aminoalkylamino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), aminosulfonyl, aminosulfonylalkyl, alkylaminosulfonyl, alkylaminosulfonylalkyl, di(alkyl)aminosulfonyl, di(alkyl)aminosulfonylalkyl, carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, trihalo substituted lower alkyl and trihalo substituted lower alkoxy;
R7 is selected from the group consisting of alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy;
R8 is selected from the group consisting of alkyl, OH, hydroxyalkyl, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, alkylcarbonylamino, alkylcarbonyl, alkoxycarbonyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, O(CH2)nR5, O(CH2)nO(CH2)mR5, O(CH2)nCH[(CH2)mR5]2, O(CH2)nN[(CH2)mR5]2, OCON[(CH2)mR5]2, NH(CH2)nR5, NH(CH2)nCH(R5)2, NH(CH2)nSO2(CH2)mR5, NH(CH2)nO(CH2)mR5, NH(CH2)nOCH[(CH2)mR5]2, NH(CH2)nO(CH2)mO(CH2)mR5, NH(CH2)nN[(CH2)mR5]2, NH(CH2)nSO2NH(CH2)mR5, NH(CH2)nCH(OH)(CH2)mR5, NH(CH2)nCH(OH)(CH2)mOR5, NH(CH2)nCH(OH)(CH2)mN[(CH2)mR5]2, NH(CH2)nCO(CH2)mN[(CH2)mR5]2, NH(CH2)nCO2(CH2)mR5]2, NH(CH2)nCO(CH2)mSO2NH(CH2)mR5, NHCO(CH2)nCH(R5)2, NHCO(CH2)nR5, NHCO(CH2)nO(CH2)mR5, NHCO(CH2)nO(CH2)mO(CH2)mR5, NHCO(CH2)nO(CH2)mCO(CH2)mR5, NHCO(CH2)nN[(CH2)mR5]2, CONH(CH2)nO(CH2)mR5, and CONH(CH2)nN[(CH2)mR5]2; wherein n is an integer from 0 to 6 and m is an integer from 0 to 4; with the proviso, that m is at least 1 when R5 is selected from the group consisting of OH, amino, alkylamino and di(alkyl)amino;
R5 is selected from the group consisting of H, OH, lower alkyl, amino, alkylamino, di(alkyl)amino, aryl, heteroaryl, biheteroaryl and heterocyclyl; wherein aryl, heteroaryl and heterocyclyl are optionally substituted with 1 to 3 substituents independently selected from the group consisting of alkyl, lower alkyl, acyl, carboxyl, aryl (optionally substituted with 1 to 5 halogen substituents), OH, halogen, cyano, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, alkylsulfonyl, aminosulfonyl, alkylaminosulfonyl and aminosulfonylalkyl; and, wherein heterocyclyl is further optionally substituted with 1 to 3 oxo substituents; and,
R3 is selected from the group consisting of H, alkyl, lower alkyl, alkoxy, lower alkoxy, alkenyl, alkynyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkoxy, aryl, arylalkyl, arylalkoxy, OH, hydroxyalkyl, halogen, cyano, nitro, amino, alkylamino, di(alkyl)amino, (hydroxyalkyl)amino, di(hydroxyalkyl)amino, carbamoyl, acyl, acylalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, acylamino, alkylsulfonyl, alkylsulfonylamino, arylsulfonylamino (wherein aryl is substituted with 1 to 3 substituents independently selected from the group consisting of cyano, halogen, hydroxy, nitro, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy), carboxyl, (hydroxyalkyl)carbonyl, (hydroxyalkoxy)carbonyl, tri(halo)substituted lower alkyl and tri(halo)substituted lower alkoxy.
In a preferred embodiment of this invention, the compounds are provided as pharmaceutical compositions comprising a pharmaceutically acceptable carrier.
The invention further relates to a method for inhibiting the vascular endothelial growth factor (VEGF) receptor tyrosine kinase comprising the step of administering a therapeutically effective amount of the compounds of this invention. In a preferred embodiment, the method is used to treat a disease selected from the group consisting of aberrant angiogenesis, tumors, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.
The invention also relates to a method of treating angiogenesis in a subject in need thereof comprising administering a therapeutically effective amount of the compounds of this invention. Methods for treating tumors, including solid-tumors is also contemplated in this invention. The invention also relates to methods of treating diabetic retinopathy in a subject in need thereof comprising administering a therapeutically effective amount of a compound of this invention. Further methods for treating rheumatoid arthritis, psoriasis and endometriosis in a subject in need thereof comprising administering a therapeutically effective amount of the compound of claim 1.
In a further method of this invention, the invention relates to a method of inhibiting the vascular endothelial growth factor (VEGF) receptor tyrosine kinase comprising the step of administering a composition of this invention. Preferred diseases associated with this method include aberrant angiogenesis, tumors, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.
The compounds of the present invention are useful in treating conditions mediated by the activity of the VEGF-R including, but not limited to, solid-tumor cancers, aberrant angiogenesis, diabetic retinopathy, rheumatoid arthritis, endometriosis and psoriasis.